Hirschsprung's disease pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
No edit summary
 
(28 intermediate revisions by 8 users not shown)
Line 1: Line 1:
<div style="-webkit-user-select: none;">
{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=1pylBKNMcnw|350}}
|-
|}
__NOTOC__
__NOTOC__
{{Hirschsprung's disease}}
{{Hirschsprung's disease}}
{{CMG}}
{{CMG}}; {{AE}} {{AY}}, {{ADG}}
 
Please help WikiDoc by adding more content here.  It's easy!  Click  [[Help:How_to_Edit_a_Page|here]]  to learn about editing.


==Overview==
==Overview==
Hirschsprung’s disease is a [[congenital]] disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation. <ref>Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [http://www.ncbi.nlm.nih.gov/pubmed/7840044]</ref>
Hirschsprung’s disease is a [[congenital]] disorder of the colon in which certain [[nerve cells]], known as [[Ganglion cell|ganglion cells]], are absent. It may cause [[chronic constipation]].
==Pathophysiology==
==Pathophysiology==
===Genetics===
===Genetics===
* In 2002 and according to a new research, the interaction between two proteins [[genetic code|encoded]] by two variant genes caused Hirschsprung’s.  
* According to a study in 2002 and more recent studies, the interaction between two [[proteins]] [[genetic code|encoded]] by two variant [[genes]] may cause Hirschsprung’s disease.  
* The [[RET proto-oncogene]] on [[chromosome 10]] was identified one of the [[gene]]s involved, and it was determined that [[mutation|dominant mutation]]s may occur within this [[gene]] leading to a loss of function for the protein it [[genetic code|encoded]].
* The [[RET proto-oncogene]] on [[chromosome 10]] was identified as one of the involved [[gene]]s; it was determined that [[mutation|dominant mutation]]s may occur within this [[gene]], leading to [[genetic code|encoded]] protein function loss.<ref name="urlThieme E-Journals - European Journal of Pediatric Surgery / Abstract">{{cite web |url=https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2008-1066115 |title=Thieme E-Journals - European Journal of Pediatric Surgery / Abstract |format= |work= |accessdate=}}</ref>
* The protein with which RET has to interact in order for Hirschsprung’s disease to develop is termed EDNRB, and is encoded by the [[gene]] ''EDNRB'' located on [[chromosome 13 (human)|chromosome 13]].  
* The protein that [[RET proto-oncogene]] has to interact to develop Hirschsprung’s disease, is termed EDNRB.
* Six other genes were discovered to be associated with Hirschsprung’s. According to the study, these genes are GDNF on [[chromosome 5 (human)|chromosome 5]], EDN3 on [[chromosome 20 (human)|chromosome 20]], SOX10 on [[chromosome 22 (human)|chromosome 22]], ECE1 on [[chromosome 1 (human)|chromosome 1]], NTN on [[chromosome 19 (human)|chromosome 19]], and SIP1 on [[chromosome 2 (human)|chromosome 2]].  
* EDRB protein encoded by the [[gene]] ''EDNRB'' located on [[chromosome 13 (human)|chromosome 13]].  
* Scientists concluded that the mode of inheritance for Hirschsprung’s is oligogenic inheritance. This means that two mutated genes interact to cause a disorder. Variations in RET and EDNRB have to coexist in order for a child to get Hirschsprung’s.
* Six other genes were discovered to be associated with Hirschsprung’s disease. These genes include: [[GDNF]] on [[chromosome 5 (human)|chromosome 5]], EDN3 on [[chromosome 20 (human)|chromosome 20]], [[SOX10]] on [[chromosome 22 (human)|chromosome 22]], ECE1 on [[chromosome 1 (human)|chromosome 1]], NTN on [[chromosome 19 (human)|chromosome 19]], and SIP1 on [[chromosome 2 (human)|chromosome 2]].  
* However, although six other genes were shown to have an effect on Hirschsprung’s, the researchers were unable to determine how they interacted with RET and EDNRB. Thus, the specifics of the origins of the disease are still not completely known.
* Scientists concluded that the mode of inheritance in Hirschsprung’s disease is oligogenic. This means that two mutated [[genes]] interact to cause the disorder. Variations in [[RET proto-oncogene|RET]] and EDNRB have to coexist to involve a child with Hirschsprung’s disease.<ref name="urlA gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics">{{cite web |url=https://www.nature.com/ng/journal/v4/n4/abs/ng0893-351.html |title=A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics |format= |work= |accessdate=}}</ref>
* More recently, syndromic cases of Hischprung's disease (that is, associated with other defects of the [[autonomic nervous system]]) were shown to be caused by mutations in the homeobox gene [[PHOX2B]].
* Although six other [[genes]] show to have an effect on Hirschsprung’s disease, the exact interaction mechanism with [[RET proto-oncogene|RET]] and EDNRB is unknown. Thus, the specifics of the disease's origin are still not completely described.
* RET codes for proteins that help the neural crest cells (which become ganglion cells) move through the digestive tract during the development of the embryo.  
* More recently, syndromic cases of Hirschprung's disease (i.e. cases associated with other defects of the [[autonomic nervous system]]) were shown to be caused by [[mutations]] in the [[homeobox gene]] [[PHOX2B]].
* EDNRB codes for proteins to actually connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to these two genes mutating so the wrong proteins are produced.  
* [[RET proto-oncogene|RET]] codes for the proteins that help [[neural crest cells]] (which become [[ganglion cells]]) move through the digestive tract during the development of the [[embryo]].  
* Research published in June of 2004 suggests that there are actually ten genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.
* EDNRB codes for the [[proteins]] that connect these [[nerve cells]] to the digestive tract. This means that the absence of certain [[nerve fibers]] in the [[colon]] could be directly related to mutation of these two [[genes]], which would lead to the wrong proteins being produced.  
* Dr. Bob Sawin of Seattle’s Children's Hospital notes that it is generally accepted in the scientific community that the gene RET is the most important gene when looking for the genetic cause of Hirschsprung’s disease.  RET can mutate in many ways, and is associated with Down syndrome. Since [[Down Syndrome]] is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome.  
* Research in June 2004 suggested that there are actually ten [[genes]] associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought genes.
* RET is also associated with [[thyroid cancer]] and [[neuroblastoma]]. Both of these disorders have also been observed in Hirschsprung’s patients with greater frequency than in the general population.   
* [[RET proto-oncogene|RET]] mutates in different ways and is associated with [[Down syndrome]]. Since [[Down syndrome]] is co-morbid with two percent of Hirschsprung’s disease cases, it is assumed that [[RET proto-oncogene|RET]] is involved strongly in both Hirschsprung's disease and [[Down syndrome|Down syndrome]].
* One function that RET controls is the travel of the [[neural crest cell]]s through the [[intestine]]s in the developing [[fetus]].  When RET mutations cause Hirschsprung’s disease, the cells start traveling through the colon, only to be stopped once the mutation occurs. The earlier the mutation of RET occurs in Hirschsprung’s disease, the more severe the disorder becomes.
* [[RET proto-oncogene|RET]] is also associated with [[thyroid cancer]] and [[neuroblastoma]]. Both of these disorders have also been seen among Hirschsprung’s disease patients with greater frequency than general population.   
* While researchers remain uncertain of the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases, (in which families have multiple affected patients) Hirschsprung’s disease exhibits autosomal dominant transmission, with the gene RET being dominant. However, in sporadic cases, Sawin notes that there has been no inheritance pattern identified.
* In the developing [[fetus]], [[RET proto-oncogene|RET]] controls the [[neural crest cell]]s traveling through the [[intestine]]s. When [[RET proto-oncogene|RET]] mutations occur, the cells that started traveling through the [[colon]], stop immigration and cause Hirschsprung’s disease. The earlier the [[RET proto-oncogene|RET]] mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes.
* Treating Hirschsprung’s is much easier than determining the genetic causes of this disorder. The only way to treat Hirschsprung’s disease is through surgery (National Digestive Diseases Information Clearinghouse). If Hirschsprung’s goes untreated, the patient can develop [[enterocolitis]], the inflammation of the small intestine and the colon. This was the cause of death of the two boys that Harald Hirschsprung observed. Surgery is now used to remove the non-functioning portion of the bowel in order to restore bowel function.
* While researchers remain uncertain about the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits [[Autosomal dominant|autosomal dominant transmission]], with dominance of  the [[RET proto-oncogene|RET]]. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern.<ref name="pmid7472925">{{cite journal |vauthors=Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger KP |title=Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study |journal=J. Pediatr. Surg. |volume=30 |issue=7 |pages=1023–6; discussion 1026–7 |year=1995 |pmid=7472925 |doi= |url=}}</ref><ref name="pmid2309705">{{cite journal |vauthors=Badner JA, Sieber WK, Garver KL, Chakravarti A |title=A genetic study of Hirschsprung disease |journal=Am. J. Hum. Genet. |volume=46 |issue=3 |pages=568–80 |year=1990 |pmid=2309705 |pmc=1683643 |doi= |url=}}</ref><ref name="pmid17965226">{{cite journal |vauthors=Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R |title=Hirschsprung disease, associated syndromes and genetics: a review |journal=J. Med. Genet. |volume=45 |issue=1 |pages=1–14 |year=2008 |pmid=17965226 |doi=10.1136/jmg.2007.053959 |url=}}</ref><ref name="pmid11106284">{{cite journal |vauthors=Parisi MA, Kapur RP |title=Genetics of Hirschsprung disease |journal=Curr. Opin. Pediatr. |volume=12 |issue=6 |pages=610–7 |year=2000 |pmid=11106284 |doi= |url=}}</ref>
* Hirschsprung's disease, hypoganglionosis, gut dysmotility, gut transit disorders and intussusception have been recorded with the dominantly inherited neurovisceral porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria).
 
* Children may require enzyme or DNA testing for these disorders as they may not produce or excrete porphyrins prepuberty.
===Microscopic pathology===
*[[Biopsy]] shows absence of [[Ganglion cells|ganglionic cells]].
*Presence of [[hypertrophy|hypertrophied]] nerve trunks in the [[lamina propria]] demonstrated by [[Acetylcholinesterase|acetylcholinesterase staining]].<ref>Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [http://www.ncbi.nlm.nih.gov/pubmed/7840044]</ref>
*[[Calretinin]] staining shows decreased [[immunofluorescence]].
{| class="wikitable"
![[Image:By Marvin 101 - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=4670973.jpg|center|400px|thumb|Histopathology of Hirschsprung's disease, also known as aganglionosis. Enzyme histochemistry showing aberrant acetylcholine esterase (AChE) - Arrows show hypertrophied nerve fibers in the lamina propria - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=4670973]]
|}


===Video: Histopathological Findings ===
===Video: Histopathological Findings ===
Line 32: Line 42:


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Needs content]]
[[Category:Disease]]
[[Category:Gastroenterology]]
[[Category:Congenital disorders]]

Latest revision as of 19:27, 7 July 2020

https://https://www.youtube.com/watch?v=1pylBKNMcnw%7C350}}

Hirschsprung's disease Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Hirschsprung's Disease from other Diseases

Epidemiology and Demographics

Risk factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory findings

Electrocardiogram

X-ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary prevention

Secondary prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hirschsprung's disease pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hirschsprung's disease pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hirschsprung's disease pathophysiology

CDC on Hirschsprung's disease pathophysiology

Hirschsprung's disease pathophysiology in the news

Blogs on Hirschsprung's disease pathophysiology

Directions to Hospitals Treating Hirschsprung's disease

Risk calculators and risk factors for Hirschsprung's disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [3], Aditya Ganti M.B.B.S. [4]

Overview

Hirschsprung’s disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent. It may cause chronic constipation.

Pathophysiology

Genetics

  • According to a study in 2002 and more recent studies, the interaction between two proteins encoded by two variant genes may cause Hirschsprung’s disease.
  • The RET proto-oncogene on chromosome 10 was identified as one of the involved genes; it was determined that dominant mutations may occur within this gene, leading to encoded protein function loss.[1]
  • The protein that RET proto-oncogene has to interact to develop Hirschsprung’s disease, is termed EDNRB.
  • EDRB protein encoded by the gene EDNRB located on chromosome 13.
  • Six other genes were discovered to be associated with Hirschsprung’s disease. These genes include: GDNF on chromosome 5, EDN3 on chromosome 20, SOX10 on chromosome 22, ECE1 on chromosome 1, NTN on chromosome 19, and SIP1 on chromosome 2.
  • Scientists concluded that the mode of inheritance in Hirschsprung’s disease is oligogenic. This means that two mutated genes interact to cause the disorder. Variations in RET and EDNRB have to coexist to involve a child with Hirschsprung’s disease.[2]
  • Although six other genes show to have an effect on Hirschsprung’s disease, the exact interaction mechanism with RET and EDNRB is unknown. Thus, the specifics of the disease's origin are still not completely described.
  • More recently, syndromic cases of Hirschprung's disease (i.e. cases associated with other defects of the autonomic nervous system) were shown to be caused by mutations in the homeobox gene PHOX2B.
  • RET codes for the proteins that help neural crest cells (which become ganglion cells) move through the digestive tract during the development of the embryo.
  • EDNRB codes for the proteins that connect these nerve cells to the digestive tract. This means that the absence of certain nerve fibers in the colon could be directly related to mutation of these two genes, which would lead to the wrong proteins being produced.
  • Research in June 2004 suggested that there are actually ten genes associated with Hirschsprung’s disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought genes.
  • RET mutates in different ways and is associated with Down syndrome. Since Down syndrome is co-morbid with two percent of Hirschsprung’s disease cases, it is assumed that RET is involved strongly in both Hirschsprung's disease and Down syndrome.
  • RET is also associated with thyroid cancer and neuroblastoma. Both of these disorders have also been seen among Hirschsprung’s disease patients with greater frequency than general population.
  • In the developing fetus, RET controls the neural crest cells traveling through the intestines. When RET mutations occur, the cells that started traveling through the colon, stop immigration and cause Hirschsprung’s disease. The earlier the RET mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes.
  • While researchers remain uncertain about the exact genetic cause of Hirschsprung’s disease, Dr. Sawin notes that in familial cases (in which families have multiple affected members), Hirschsprung’s disease exhibits autosomal dominant transmission, with dominance of the RET. However, in sporadic cases, Sawin notes that there is no identified inheritance pattern.[3][4][5][6]

Microscopic pathology

Histopathology of Hirschsprung's disease, also known as aganglionosis. Enzyme histochemistry showing aberrant acetylcholine esterase (AChE) - Arrows show hypertrophied nerve fibers in the lamina propria - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=4670973

Video: Histopathological Findings

{{#ev:youtube|v3mfl0l6Tdo}}

References

  1. ↑ "Thieme E-Journals - European Journal of Pediatric Surgery / Abstract".
  2. ↑ "A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10 - Nature Genetics".
  3. ↑ Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger KP (1995). "Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study". J. Pediatr. Surg. 30 (7): 1023–6, discussion 1026–7. PMID 7472925.
  4. ↑ Badner JA, Sieber WK, Garver KL, Chakravarti A (1990). "A genetic study of Hirschsprung disease". Am. J. Hum. Genet. 46 (3): 568–80. PMC 1683643. PMID 2309705.
  5. ↑ Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R (2008). "Hirschsprung disease, associated syndromes and genetics: a review". J. Med. Genet. 45 (1): 1–14. doi:10.1136/jmg.2007.053959. PMID 17965226.
  6. ↑ Parisi MA, Kapur RP (2000). "Genetics of Hirschsprung disease". Curr. Opin. Pediatr. 12 (6): 610–7. PMID 11106284.
  7. ↑ Worman and Ganiats 1995, Am Fam Physician 51, 487-494 [1]
Retrieved from "https://www.wikidoc.org/index.php?title=Hirschsprung%27s_disease_pathophysiology&oldid=1622240"